Levodopa and dopamine have been shown in preclinical studies to be effective antitumor agents against experimental melanoma. A characteristic biochemical effect of these drugs upon tumor cells has been a rapid and complete inhibition of thymidine incorporation. Experimental data available is consistent with the hypothesis that inhibition of DNA polymerase is a likely site of action. We have taken advantage of the fact that each of these agents has had extensive clinical use in humans to evaluate the potential significance of these results. The objectives of this project, therefore, would be 1) to determine if cytotoxic levels of these drugs can be achieved in humans, 2) to determine if a biochemical effect upon the tumor (i.e., inhibition of thymidine incorporation) can be observed, and 3) to determine if a therapeutic response (i.e., tumor regression) can be achieved. In preparation for this undertaking we have obtained full approval of a protocol to achieve the above results and have already treated 5 patients with advanced disease. Plasma levels in these patients have been monitored by a high pressure liquid chromatography assay and preliminary results suggest that cytotoxic levels can be achieved. We have also biopsied tumor nodules in one patient before and after treatment and observed a significant drop in labeling index. One of the patients has been treated long enough to observe a tumor response. This work is important because malignant melanoma is highly resistant tumor for which new agents are critically needed. We feel we are in a unique position to rapidly evaluate the potential clinical significance of these findings.